1-Substituted -6-(2-hydroxy-3-substituted aminopropoxy)xanthen-9-ones

ABSTRACT

The disclosure is directed to 1-substituted-6-(2-hydroxy-3substituted aminopropoxy)xanthen-9-ones which have the formula   WHERE R1 is hydrogen or di(lower)alkylamino(lower)alkyl; and R2 and R3 when taken separately are hydrogen or lower alkyl and when taken together with the nitrogen atom to which they are attached are morpholino, piperazino, N-lower alkyl-piperazino, piperidino, lower alkylpiperidino and phen(lower)alkyl piperidino. The compounds exhibit antiarrhythmic activity when evaluated in standard pharmacological procedures or are intermediates in the preparation of compounds having antiarrhythmic activity. Also some of the compounds have anti inflammatory activity.

' United States Patent [191 Santilli et a1. 7

[451 Oct. 14,1975

7 [22] Filed:

1 5 4 I 1 SUBSTITUTED -6- Z-HYDROXY-S-SUBSTITUTED AMINOPROPOXY )XANTIIEN-9-ONES [75) inventors: Arthur. Santilli, Havertown;

Anthony C. Scotese, King of Prussia; Stanley C. Bell, Penn Valley, all of Pa.

[7 3] Aanlgnee: American Home iroducia Corporation, New York. NY.

May 8, 1974 [21] Appl. No.: 468,053

[52] US. Cl...................260/247.5 H, 260/247.7 S, 260/268 TR; 260/293.58;

, [51] Int. Cl. .C07D 295/00; C07D 311/86 [58] Field of Search 260/247.5 H, 247.7 S, 335, 260/293.58, 268 TR (56] References Cited UNITED STATES PATENTS 3,340,260 9/1967 Howe et al 260/335 FOREIGN PATENTS OR APPLICATIONS OTHER PUBLICATIONS Drake, Journal of Medicinal Chemistry, i972, Vol. 15, No. 8. pp. 868-869.

2/1972 South Africa 260/246 B Primary Etamx'ncr-Robert Gersti Assistant Examiner-Richard D. Kelly Attorney, Agent, or Firm-Joseph Martin Weigman ABSTRACT The disclosure -is directed to l-subst1tutcd-6-(2- 'hydroxy-Zi-aubatltuted nmlnopropoxy)xanthen-9-ones which have the formula R 0a ncn ttca o 0 2 I where R, is hydrogen or 9 Claim, 1 Drawing Figure This invention relates to new and useful l,6-bissubstituted xanthen-9-ones and their pharmaceutically acceptable addition salts. The chemical structure of the compounds may be schematically represented by acs csca o then-9-one, hydrochloride. hemihydrate'. l-(2- dicthylaminoethoxy)-6-(3-diethylamino-2- hydroxypropoxy)xanthen-9-one and l-(2- diethylaminocthoxy)-6-(2-hydroxy-3- morpholinopropoxy)xanthen-9-one.

The preparation of the compounds may be represented schematically by the flow diagram shown in FIG. I where R.. R, and R are as described above, and R, is

NCH3 I -0-or The closest known prior art is U.S. Pat. No. 3.340.266.

The starting material l.6-dihydroxy-9-oxoxanthene is described in P. K. Grover, G. D. Shah and R. C. Shah. J. Chem. Soc. 3982 (i966).

The compound having formula III of FIG. 1 may be prepared as follows. A mixture of l.6-dihydroxy-9- oxoxanthene in epichlorohydrin containing a few drops of piperidine is heated at l00 to l28C for l to 3 hours. preferable at reflux for about one and one half hours. The mixture is cooled in ice yielding the product 6-( 2-epoxypropoxy)- l -hydroxyxanthene-Q-one which is recovered and purified. I

Compounds having formula IV of FIG. 1 may be prepared as follows. A mixture of 6-(2-cpoxypropoxy)-lhydroxyxanthen-Q-one and lower alkylamlne in an inert organic solvent, such as ethanol, is heated at 70 to 90C for 2 to 4 hours, preferably at reflux for about 3 hours. The solvent is removed. for instance by evaporation. The residue is triturated in an appropriate medium, such as ethyl acetate, and filtered. The filtrate is acidified. for example with alcoholic hydrochloric acid solution. and precipitation induced, if necessary, to yield the product 6-(3-lower alkylamino-2- hydroxypropoxy)-l-hydroxyxanthen-9-one, which is recovered and purified.

Compounds having formula V of FIG. I may be prepared as follows. A mixture of 6-(3-lower alkylamino- 2-hydroxyproxy)- l -hydroxyxanthen-9-one. halotri( lower)alkylamine and a strong base. such as an aqueous solution of sodium hydroxide, in an inert organic solvent.'such as xylene is iheated at 120 to l50C for 4 to 8 hours. preferably at reflux for about 6 hours with the water being removed by azeotropie distillation. The mixture is filtered and the filtrate extracted with a strong acid, such as l0 percent aqueous hydrochloric acid. The water layer is basified, for example with concentrated ammonium hydroxide, and extracted with an organic solvent. such as ether. The organic layer is dried, for example over magnesium sulfate. and removed, for example by evaporation, and crystallized by trituration in an appropriate medium, such as petroleum ether, to yield the product l-(2 di(lower)alkylamino(lower)alkoxy)-6 3-l0wer alkylamino-2-hydroxypropoxy)xanthen-9-one. which is recovered and purified.

Compounds having formula Vi of FlG. i may be prepared as follows. A mixture of 6-(2-epoxypropoxy)- l hydroxyxanthen-9-one and morpholine in an inert solvent. such as ethanol, is heated at to C for 2 to 4 hours, preferably at reflux for about 3 hours. The solvent is removed, for example by evaporation. and the residue mixed with a solvent, for example ethyl acetate. and filtered. The filtrate is diluted, for example with petroleum ether and cooled. Precipitation is induced and the precipitate collected and purified to yield a product of formula VI, such as l-hydroxy-6-(2-hydroxy-3- morpholinopropoxy)xanthen-9-one.

Compounds having formula VII of FIG. I may be prepared as follows. A stirred mixture of l-hydroxy-6- (2-hydroxy-3-morpholinopropoxy)xanthen-9-one halotri(lower)alkylamine and a strong base. such as an aqueous solution of sodium hydroxide, is heated at l20 to l50C for 4 to 8 hours, preferably at reflux for about 6 hours, with the water removed by azeotropic distillation. The mixture is filtered and the filtrate extracted with a strong acid, such as ten percent aqueous hydrochloric acid. The water layer is basified. for example with concentrated ammonium hydroxide and extracted with an organic solvent. such as chloroform The chloroform layer is removed and the residue purified to yield the product l-[ 2- di(lower)alkylaminoalkoxy1-6-(2-hydroxy-3- morpholinopropoxy)xanthen-9-one.

in the pharmacological evaluation of the biological activity of the compounds of this invention, the in vivo effects are tested as follows. The heart of an anesthetized dog is exposed by a left thoracotomy. Bipolar electrodes are sutured to the epieardial surface of the left ventricle. The heart is stimulated with square wave pulses of 2-3 milliseconds duration and frequency of 60 hertz for periods of 5 seconds. The voltage is increased until fibrillation ensues. The heart in then delithreshold examined i minutes after start of injection" of each dose. Effective antiarrhythmie agents elevate the fibrillatory threshold. Drugs must be soluble in water or in a 50 percent mixture of polyethylene glycol 400 and water to'the extent of percent. Useful new antiarrhythmic substances should exert only minimal depressant activity on systemicblood pressure, myo cardial contractility and conduction. Standard compounds are quinidine, procainamide, lidocaine, pro

pranolol, diphcnylhydantoin.

The compounds of the present invention which are effective antiarrhythmic agents may be administered at a dose of 300 milligrams three or four times per day.

The evaluation of activity as anti-inflammatory and immunosuppressive agents is carried out as follows: Polyarthritis is induced in male Lewis strain rats 150-200 g) by the injection of a suspension of tubercle bacilli in mineral oil in the subplantar tissue of the right hind paw. Drug therapy is either begun on the day of antigen or can be started after appearance of an established arthritic syndrome 14 days). Compounds are administered daily in the form of a fine suspension by stomach tube. Body weights, left and injected right paw volumes and occurence of arthritic nodules on the ears, tail and front paws are detemtined at frequent intervals over a 14 to 21 day period. All animals are then autopsied and stress organ weights, hematology, histopathology and biochemical studies on blood proteins are done. Active compounds will either prevent or reverse the joint swelling and associated sequella of polyarthritis with minimal toxicity.

Compounds used as standards are Cortisone, phenylbutazone, indomethacin. aspirin, and 6- mercaptopourine. Literature references are: Newbould, B. B. Brit. J. Plrarm. C/remurh. 2 l t l 27, i963 and Rosenthale, M. E. and Nagra, C. L. Proc. Soc. exp Biol. and Med. l25tl49, 1967.

When the compounds of this invention are employed as described above, they may be administered alone or in combination with pharmacologically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk, sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups; and then dehydrated sufficiently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that .is intra-muscularly, intraveneousiy or subcutaneously.

For parental administration they maybe used in the form of a sterile solution containing other solutes, for

example, enough saline or glucose to make the solution 4 the dosage is increased by small increments until the optimum effect under the circumstances is reached. it will generally be found that when the composition is administered orally, larger quantities of the active ME CHNHCH CH (OH) CH 0 agent will be required to produce the same effect as a smaller quantity given parenterally. in general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.

in order more clearly to disclose the nature of the present invention, specific examples of the practice of theinvention are hereinafter given. it should be understood, however. that this is done solely by way of example and is intended neither to delineate the scope of the invention nor limit the ambit of the appended claims. in the examples. all temperatures are stated in degrees Centigrade, and the following abbreviations are used: "g for grams, "ml for milliliters, "min for minutes and hr for hours.

EXAMPLE I This example illustrates the: preparation of 6-(2- epoxypropoxy)-l-hydroxyxanthen-9-one, an intermediate having formula ill:

0 OH i CH -CHCH O o A mixture of i5 g of l,6-dihydroxy-9-oxoxanthene in 150 ml of epichlorohydrin containing afew drops of piperidine was heated under refllux for L5 hours. The mixture on cooling in ice deposited a solid which was collected and dissolved in chloroform. Dilution with petroleum ether resulted in a precipitate having a melting point of l52-l54.

Anal. Calcd for C H O C, 67.60; H, 4.26. Found: C, 66.28; H, 4.34.

The product was used without purification to prepare derivatives as described in the following examples.

EXAMPLE Ii This example illustrates the preparation of lhydroxy-6-(Z-hydroxy-3-isopropylaminopropoxy)xanthen-9-one, hydrochloride, hemihydrate a compound of formula IV:

A mixture of 7 g of 6-(2-epoxypropoxy)- i -hydroxyxanthen-9-one and 20 mi of isopropyiamine in lOO ml of insoluble particles. the filtrate was acidified with alcoholic hydrochloric acid solution. Anhydrous ether was added to induce precipitation. The precipitate was collected and recrystallized from ethanol with ether used for inducing precipitation to give 2.4 g of product having a melting point of 255-"60.

Based on the assumed molecular formula C H- ClNO. l/2H O it was calculated that the elemental analysis by weight would be 58.69 percent carbon. 5.96 percent hydrogen and 3.60 percent nitrogen. The product was analyzed and found to contain 58.57percent carbon, 6.05 percent hydrogen and 3.72 percent nitrogen which confirmed with accuracy of the assumed formula. This may be expressed:

Anal. Calcd for C l-l- ClNOs l/2H O: C. 58.69; H,

5.96; N. 3.60. Found: C, 58.57: H, 6.05; N, 3.72.

The compound when evaluated in the foregoing pharmacological procedure showed a 26 percent protection against acute inflammation at a dose of 25 MPK administered seven times daily for 2 days.

The compound also showed a 28 percent protection against delayed hypersensitivity at a dose of 75 MPK administered seven times daily.

EXAMPLE lll This example illustrates the preparation of 6-(3- diethylamino-2-hydroxypropoxy)-l-hydroxyxanthcn- 9-one. hydrochloride, a compound of formula IV:

A mixture of5 g of 6-(2-epoxypropoxy)-l-hydroxyxanthen-J-one and 20 ml of diethylamine in l ml of ethanol was heated under reflux for 3.5 hours. The ethanol was removed in a rotary evaporator and the residue triturated with I50 ml of ethyl acetate. The mixture was filtered and the filtrate acidified with alcoholic hydrochloric acid solution. The precipitate was collected and recrystallized from ethanol using ether-to induce precipitation to give 3.0 g of product having a melting point of l96-200".

Anal. Calcd for C H NOhCl: C. 60.99; H, 6J4; N. 3.55; CI. 9.00. Found: C. 6l.02; H. 6J8; N, 3.65; CI, 8.94.

The compound was found to produce a 97 percent kill of Trlclromunus.vaginalis strain ATCC No. 13972 at a dose of l milligram per milliliter.

EXAMPLE IV This example illustrates the preparation of lhydroxy-6-[2-hydroxy-3-(4-methyl-lpiperazinyl)propoxyIxanthen-9-one, dihydrochloride.

hydrate, a compound of formula IV:

ZliCl To a suspension of 7 g of 6-(2-epoxypropoxy)-lhydroxyxanthen-9-one in. i00 ml of ethanol was added 20 ml of N-methylpiperazine. The mixture was refluxed for 3 hours. The ethanol was evaporated in a rotary evaporator and the residue was triturated with ISO ml of ethyl acetate. After filtering ofi the insoluble material, the filtrate was acidified with ethereal hydrochlorie acid solution and cooled in ice. The precipitate thus formed was collected and recrystallized twice from ethyl acetate to afford 2.8 g of product which decomposed at 262-266.

Anal. Calcd for C H N- o Cl C. 53.06; H, 5.94: N.

5.89. Found: C. 53.04; H, 5.90; N, 5.83.

EXAMPLE V ca -O1ca ca (0a) ca o To a suspension of i0 g of 6-(2-epoxypropoxy)-lhydroxyxanthen-J-one in 250 ml of ethanol was added 20 ml of 4-benzylpiperidline. The mixture was heated under reflux f0r,3 hours. The mixture was filtered and the filtrate cooled in ice. The precipitate thus formed was collected and recrystallized from ethyl acetate to give 4.8 g of product having a melting point of l46- 149.

Anal. Calcd for C ,.H ,,NO C, 73.18; H, 6.36; N.

' 3.05. Found: c. 73.05; H, 6.45; N. 3.04.

When evaluated in the foregoing pharmacological procedure the compound was found to produce a slight increase in fibrillatory threshold at a dose of 20'MPK.

The compound also showed 26 percent protection against acute inflammation at a dose of MPK administered seven times daily.

EXAMPLE Vl This example illustrates the preparation of l-(?.- diethylaminoethoxy )-6-( 3-diethylamino-2- hydroxypropoxy)xanthen-9-one, a compound of formula V:

OCH CH NEt A mixture of 6.4 g of 6-(3-dlethylamino-2- hydroxypropoxyi-l-hytlroxyxanthen-9-one. 3.l g oi 2- ehlorotrlethylamlne hydrochloride and 2.9 g of 50 percent sodium hydroxide in 500 ml of xylene was heated under reflux for 6 hours with the water being removed by azeotropic distillation. The reaction mixture was filtered and the filtrate extracted with 300 mi of it) percent aqueous hydrochloric acid solution. The water layer was basified to pH 9 with concentrated ammonium hydroxide and extracted with ether. The ether layer after drying over magnesium sulfate was removed in a rotary evaporator and the residue crystallized by trituration with petroleum ether. This solid was collected and recrystallized from heptane after treatment with charcoal to give 3.7 g of product having a melting point of 94-96.

Anal. Calcd for C H MO C. 68.39: H. 7.95: N.

(xi-i. Found: C. 68.59; H. 7.78: N. 6.20. Following the foregoing procedure but substituting an appropriate halotrl (lower)alkylamine the corresponding i-dimethylaminomethoxy and l-(3- dipropylaminopropoxy) derivatives may be prepared.

When evaluated in the foregoing pharmacological procedure the compound was found to produce a slight increase in fibrillatory threshold of all hosts and a large increase in one third of the hosts at a dose of 20 MPK. When evaluated in the foregoing pharmacological procedure the compound showed. at a dose of lOO MPK administered five times daily. 4i percent protection against acute inflammation and 38 percent protection against delayed inflammation and 56 percent protection against delayed hypersensitivity.

EXAMPLE Vll This example illustrates the preparation of l-(2- I diethylaminoethoxy)-6-(2-hydroxy-3- isopropylaminopropoxy)xanthen-9-one. dihydrochloride. hemihydrate. a compound of formula V:

O OCH CH NEt Me cilNlicil CiHOIUCH O l/2ll lected. dried and recrystallized from ethanol with pctroleum ether used for precipitation affording 4.7 g of product which decomposed at 243-246.

Anal. Calcd forC ,-,H.,..N,Cl.,O l/2H O: C. 57.25: H. 7.l l; N. 5.34. Found: C. 57.15: H. 7J2; N. 5.40.

When evaluated in the foregoing pharmacological procedure the compound was found to produce a marked increase in the fihrillatory threshold of the host at a dose of 20 MPK.

The compound was found to produce a 97 percent kill ol 'l'riclmmrnms vagina/ix strain ATCC No. l3")72 at a dose of l milligram per milliliter.

EXAMPLE Vlll 0 NCH CiHOlUCH O A mixture of i0 g of 6-(2-epoxypropoxy)-l-hydroxl yxanthen-9-one and ml of morpholine in 200 ml of ethanol was heated under reflux for 3 hours. The ethanol was removed in a rotary evaporator and the residue was treated with ethyl acetate and filtered. The filtrate after dilution with petroleum ether was cooled in ice. The oil which separated crystallized on scratching. Collection of the solid and recrystallization of the filter cake resulted in 8 g of product having a melting point of l28-l3l.

Anal. Calcd for C H NO C. 64.68; H. 5.70: N.

3.77. Found: C. 64.2l: H. 5.73; N. 3.4l

EXAMPLE IX This example illustrates the preparation of l-(2- diethylaminoethoxy )-6-( 2-hydroxy-3- 30 morpholinopropoxy)xanthen-9-one'. a compound of formula VI]:

A stirred mixture of 8.1 gof l-hydroxy-6-( 2-hydroxy- 3-morpholinopropoxy)xanthen-Q-one. 3.4 g of 2- chlorotriethylamine hydrochloride and 3.2 g of percent sodium hydroxide was heated under reflux in 500 ml of xylene for 6 hours with the water being removed by azeotropic distillation. The mixture was filtered and the filtrate extracted with 300 ml of i0 percent aqueous hydrochloric acid. The water layer was basified with concentrated ammonium hydroxide and extracted with 200 ml of chloroform. The chloroform layer was dried over magnesium sulfate. filtered and evaporated in a rotary evaporator. The residue was recrystallized from ethyl acetate to give 3.0) g of product having a melting point of l20-l22.

Anal. Calcd for C H N O C, 66.36; H. 7.28; N.

5.95. Found: C. 66.25; H. 7.09; N. 5.77.

Following the foregoing procedure but substituting an appropriate halotri(lower)alkylamine the corresponding l-dimcthylaminomethoxy and l-( 3- dipropylaminoprt'ipoxy) derivatives may be prepared.

When evaluated in the foregoing pharmacological procedure the compound was found to produce a borm derline increase in threshold hypertension at a dose of 20 MiK.

The compound showed 4i percent protection against acute inflammation at a dose of MPK administered five times daily and a 38 percent protection against delayed inflammation at a dose of 75 MPK administered five times daily.

What is claimed is:

l. A compound selected from those having the formula NCH CHCH O 0 10 hydroxy-6(2-hydroxy-3-isopropylaminopropoxy)xanthen-9-one. hydrochloride, hemihydrate.

3. A compound as defined in claim I which is 6-(3- diethylamino-Z-hydroxypropoxy l -hydroxyxanthen- 9-one\ hydrochloride.

4. A compound as defined in claim 1 which is lhydroxy-6-[ 2-hydr0xy-3-( 4-methyll piperazinyl)propoxylxanthen-9-one, dihydrochloride. hydrate.

5. A compound as defined in claim 1 which is 6-[ 3- (4-benzylpiperidino)-2-hydroxypropoxy]- l -hydroxyxanthen-9-one.

6 A compound as defined in claim 1 which is l-(2- diethylaminoeth'oxy )-6( 3-diethylamino-2- hydroxypropoxy)xanthen-9-one.

7. A compound as defined in claim 1 which is l-( 2- diethylaminoethoxy )-6-( 2-h ydroxy-3- isopropylaminopropoxy)xanthen-9-one, dihydrochloride. hemihydrate.

8. A compound as defined in claim I which is l'(2- diethylaminoethoxy )-6-( 2-hydroxy-3- morpholinopropoxy )xanthen-9-one.

9. A compound as defined in claim 1 which is lhydroxy-6-( 2-hydr0xy-3-morpholinopropoxy )xanthen- 9-one.

* a i w 

1. A COMPOUND SELECTED FROM THOSE HAVING THE FORMULA
 2. A compound as defined in claim 1 which is 1-hydroxy-6-(2-hydroxy-3-isopropylaminopropoxy)xanthen-9-one, hydrochloride, hemihydrate.
 3. A compound as defined in claim 1 which is 6-(3-diethylamino-2-hydroxypropoxy)-1-hydroxyxanthen-9-one, hydrochloride.
 4. A compound as defined in claim 1 which is 1-hydroxy-6-(2-hydroxy-3-(4-methyl-1-piperazinyl)propoxy)xanthen-9-one, dihydrochloride, hydrate.
 5. A compound as defined in claim 1 which is 6-(3-(4-benzylpiperidino)-2-hydroxypropoxy)-1-hydroxyxanthen-9-one.
 6. A compound as defined in claim 1 which is 1-(2-diethylaminoethoxy)-6-(3-diethylamino-2-hydroxypropoxy)xanthen-9-one.
 7. A compound as defined in claim 1 which is 1-(2-diethylaminoethoxy)-6-(2-hydroxy-3-isopropylaminopropoxy)xanthen-9-one, dihydrochloride, hemihydrate.
 8. A compound as defined in claim 1 which is 1-(2-diethylaminoethoxy)-6-(2-hydroxy-3-morpholinopropoxy)xanthen-9-one.
 9. A compound as defined in claim 1 which is 1-hydroxy-6-(2-hydroxy-3-morpholinopropoxy)xanthen-9-one. 